Individuals with anorexia nervosa (AN) have aberrant feeding behavior, disturbances of emotionality and impulse control, and have high rates of relapse after weight restoration1, 2. There is no proven treatment that reverses symptoms. Although imaging studies in individuals recovered from AN suggest that these symptoms are related to dysfunction of the striatal, insular, and prefrontal areas, less is known about the biology of these core symptoms in currently ill individuals. This application will use blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to examine neural substrates underlying appetitive, reward, and cognitive dysregulation in ill AN. We will study 20 adolescent women currently ill with AN and 20 healthy adolescent control women (CW), all of whom are 14 to 18 years old. AIM 1: The anterior insula (AI), orbitofrontal cortex (OFC), and associated regions integrate sensory/hedonic aspects of taste and interoceptive awareness in the service of homeostasis. We hypothesize that restricted eating and weight loss occur in AN because a palatable food elicits little reward. AIM 2: Little in life is rewarding to individuals with AN aside from weight loss, and they tend to be overconcerned with future consequences. We predict that ill AN will show an inability to discriminate positive and negative feedback reflecting aberrant anterior ventral striatum (AVS) limbic function. AIM 3: AN tend to be rigid, inflexible and behaviorally inhibited. We will use a stop task3-5 to characterize the neural substrates of inhibitory motor control. We hypothesize that ill AN, relative to CW, will show a demand-specific alteration of a fronto- subthalamic circuit that is necessary for motor inhibition6. Finally, in an Exploratory Aim, we propose to examine how clinical, cognitive, and personality/temperament measures might be correlated to either the BOLD response and/or the integrity of frontostriatal connectivity as determined using diffusion tensor imaging (DTI). Taken together, these aims will enable us to better characterize cognitive and limbic dysfunction in these populations. Understanding biologic vulnerabilities in AN is critical for developing effective treatment interventions for this often chronic and deadly disorder. In addition, there is a lack of understanding of appropriate methodologies necessary to address the unique problems inherent in the study of ill AN. Thus, this R21 application will also characterize confounding factors, such as brain volume, energy metabolism, development stages, and gonadal steroids, with the intent that a future R01 application will incorporate methodology needed to rigorously investigate this population. PUBLIC HEALTH RELEVANCE: There is considerable evidence that alterations in brain function contribute to disturbances of appetite, emotionality, and impulse control in anorexia nervosa. This application will use functional magnetic brain imaging to characterize neuronal circuits and their relationship to behavior. Understanding the pathophysiology of anorexia nervosa is necessary in order to devise new and more effective treatment interventions for this often chronic and deadly disorder.